Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates β-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.
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Harris, P.C. Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1. Curr. Opin. Nephrol. Hypertens. 11, 309–314 (2002).
Hildebrandt, F. & Zhou, W. Nephronophthisis-associated ciliopathies. J. Am. Soc. Nephrol. 18, 1855–1871 (2007).
Simons, M. et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet. 37, 537–543 (2005).
Bergmann, C. et al. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber–like syndrome, situs inversus,and renal-hepatic-pancreatic dysplasia. Am. J. Hum. Genet. 82, 959–970 (2008).
Saadi-Kheddouci, S. et al. Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the β-catenin gene. Oncogene 20, 5972–5981 (2001).
Qian, C.N. et al. Cystic renal neoplasia following conditional inactivation of apc in mouse renal tubular epithelium. J. Biol. Chem. 280, 3938–3945 (2005).
Marose, T.D., Merkel, C.E., McMahon, A.P. & Carroll, T.J. β-catenin is necessary to keep cells of ureteric bud/Wolffian duct epithelium in a precursor state. Dev. Biol. 314, 112–126 (2008).
Pinson, K.I., Brennan, J., Monkley, S., Avery, B.J. & Skarnes, W.C. An LDL-receptor–related protein mediates Wnt signalling in mice. Nature 407, 535–538 (2000).
Ferland, R.J. et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat. Genet. 36, 1008–1013 (2004).
Dixon-Salazar, T. et al. Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am. J. Hum. Genet. 75, 979–987 (2004).
Louie, C.M. & Gleeson, J.G. Genetic basis of Joubert syndrome and related disorders of cerebellar development. Hum. Mol. Genet. 14 Spec No. 2, R235–R242 (2005).
Utsch, B. et al. Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome. Pediatr. Nephrol. 21, 32–35 (2006).
Rauchman, M.I., Nigam, S.K., Delpire, E. & Gullans, S.R. An osmotically tolerant inner medullary collecting duct cell line from an SV40 transgenic mouse. Am. J. Physiol. 265, F416–F424 (1993).
Eley, L. et al. Jouberin localizes to collecting ducts and interacts with nephrocystin-1. Kidney Int. 74, 1139–1149 (2008).
Davison, A.M. et al. Oxford Textbook of Clinical Nephrology Section 16.3 (Oxford University Press, Oxford, 2005).
Faraggiana, T., Malchiodi, F., Prado, A. & Churg, J. Lectin-peroxidase conjugate reactivity in normal human kidney. J. Histochem. Cytochem. 30, 451–458 (1982).
Patel, V. et al. Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum. Mol. Genet. 17, 1578–1590 (2008).
Attanasio, M. et al. Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat. Genet. 39, 1018–1024 (2007).
Kim, Y.S. et al. Kruppel-like zinc finger protein Glis2 is essential for the maintenance of normal renal functions. Mol. Cell. Biol. 28, 2358–2367 (2008).
Krishnan, R., Eley, L. & Sayer, J.A. Urinary concentration defects and mechanisms underlying nephronophthisis. Kidney Blood Press. Res. 31, 152–162 (2008).
Parisi, M.A. et al. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J. Med. Genet. 43, 334–339 (2006).
Badano, J.L., Mitsuma, N., Beales, P.L. & Katsanis, N. The ciliopathies: an emerging class of human genetic disorders. Annu. Rev. Genomics Hum. Genet. 7, 125–148 (2006).
Kim, Y.S., Kang, H.S. & Jetten, A.M. The Kruppel-like zinc finger protein Glis2 functions as a negative modulator of the Wnt/β-catenin signaling pathway. FEBS Lett. 581, 858–864 (2007).
Zhang, K. et al. PKD1 inhibits cancer cells migration and invasion via Wnt signaling pathway in vitro. Cell Biochem. Funct. 25, 767–774 (2007).
Kim, E. et al. The polycystic kidney disease 1 gene product modulates Wnt signaling. J. Biol. Chem. 274, 4947–4953 (1999).
Zheng, R. et al. Polycystin-1 induced apoptosis and cell cycle arrest in G0/G1 phase in cancer cells. Cell Biol. Int. 32, 427–435 (2008).
Lal, M. et al. Polycystin-1 C-terminal tail associates with β-catenin and inhibits canonical Wnt signaling. Hum. Mol. Genet. 17, 3105–3117 (2008).
DasGupta, R. & Fuchs, E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557–4568 (1999).
Iglesias, D.M. et al. Canonical WNT signaling during kidney development. Am. J. Physiol. Renal Physiol. 293, F494–F500 (2007).
Weiss, D.J., Liggitt, D. & Clark, J.G. Histochemical discrimination of endogenous mammalian β-galactosidase activity from that resulting from lac-Z gene expression. Histochem. J. 31, 231–236 (1999).
Duffield, J.S. et al. Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow–derived stem cells. J. Clin. Invest. 115, 1743–1755 (2005).
Maretto, S. et al. Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors. Proc. Natl. Acad. Sci. USA 100, 3299–3304 (2003).
Filali, M., Cheng, N., Abbott, D., Leontiev, V. & Engelhardt, J.F. Wnt-3A/β-catenin signaling induces transcription from the LEF-1 promoter. J. Biol. Chem. 277, 33398–33410 (2002).
Jho, E.H. et al. Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol. Cell. Biol. 22, 1172–1183 (2002).
Niida, A. et al. DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin/TCF pathway. Oncogene 23, 8520–8526 (2004).
Hovanes, K. β-catenin–sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat. Genet. 28, 53–57 (2001).
Li, C.M. et al. CTNNB1 mutations and overexpression of Wnt/β-catenin target genes in WT1-mutant Wilms' tumors. Am. J. Pathol. 165, 1943–1953 (2004).
Takada, S. et al. Wnt-3a regulates somite and tailbud formation in the mouse embryo. Genes Dev. 8, 174–189 (1994).
Korinek, V. et al. Constitutive transcriptional activation by a β-catenin–Tcf complex in APC−/− colon carcinoma. Science 275, 1784–1787 (1997).
Kaykas, A. et al. Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Nat. Cell Biol. 6, 52–58 (2004).
Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).
Willert, K. & Nusse, R. β-catenin: a key mediator of Wnt signaling. Curr. Opin. Genet. Dev. 8, 95–102 (1998).
van Noort, M., Meeldijk, J., van der Zee, R., Destree, O. & Clevers, H. Wnt signaling controls the phosphorylation status of β-catenin. J. Biol. Chem. 277, 17901–17905 (2002).
Cokol, M., Nair, R. & Rost, B. Finding nuclear localization signals. EMBO Rep. 1, 411–415 (2000).
Surendran, K., Schiavi, S. & Hruska, K.A. Wnt-dependent β-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J. Am. Soc. Nephrol. 16, 2373–2384 (2005).
Meldrum, K.K., Meldrum, D.R., Meng, X., Ao, L. & Harken, A.H. TNF-α–dependent bilateral renal injury is induced by unilateral renal ischemia-reperfusion. Am. J. Physiol. Heart Circ. Physiol. 282, H540–H546 (2002).
Jauregui, A.R., Nguyen, K.C., Hall, D.H. & Barr, M.M. The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. J. Cell Biol. 180, 973–988 (2008).
Schmidt-Ott, K.M. & Barasch, J. WNT/β-catenin signaling in nephron progenitors and their epithelial progeny. Kidney Int. 74, 1004–1008 (2008).
Kuure, S., Popsueva, A., Jakobson, M., Sainio, K. & Sariola, H. Glycogen synthase kinase-3 inactivation and stabilization of β-catenin induce nephron differentiation in isolated mouse and rat kidney mesenchymes. J. Am. Soc. Nephrol. 18, 1130–1139 (2007).
Park, J.S., Valerius, M.T. & McMahon, A.P. Wnt/β-catenin signaling regulates nephron induction during mouse kidney development. Development 134, 2533–2539 (2007).
Osafune, K., Takasato, M., Kispert, A., Asashima, M. & Nishinakamura, R. Identification of multipotent progenitors in the embryonic mouse kidney by a novel colony-forming assay. Development 133, 151–161 (2006).
Saburi, S. et al. Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nat. Genet. 40, 1010–1015 (2008).
Kishimoto, N., Cao, Y., Park, A. & Sun, Z. Cystic kidney gene seahorse regulates cilia-mediated processes and Wnt pathways. Dev. Cell 14, 954–961 (2008).
Bonventre, J.V. & Zuk, A. Ischemic acute renal failure: an inflammatory disease? Kidney Int. 66, 480–485 (2004).
Bonventre, J.V. Dedifferentiation and proliferation of surviving epithelial cells in acute renal failure. J. Am. Soc. Nephrol. 14 Suppl 1, S55–S61 (2003).
Davenport, J.R. et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr. Biol. 17, 1586–1594 (2007).
Piontek, K., Menezes, L.F., Garcia-Gonzalez, M.A., Huso, D.L. & Germino, G.G. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490–1495 (2007).
Calvet, J.P. Injury and development in polycystic kidney disease. Curr. Opin. Nephrol. Hypertens. 3, 340–348 (1994).
We are grateful to members of the Gleeson lab for technical expertise and feedback and the Nigam lab for helpful kidney-related discussions and reagents, as well as B. Brinkman and the UCSD Neuroscience Microscopy Core. We also thank the K. Kaushansky, M. Karin, and P.L. Mellon labs, as well as E.L. Stone for technical expertise. We are grateful to S. Piccolo at the Departments of Histology, Microbiology and Medical Biotechnologies, University of Padua, for the BATGAL mice. We thank S. Pleasure at the Department of Neurology, University of California–San Francisco, for Lrp6-mutant mice. We also thank M.G. Rosenfeld at the School of Medicine, UCSD, for the β-catΔN construct and R.T. Moon at the Department of Pharmacology, University of Washington, for the Super Topflash construct. M.A.L. and C.M.L received support from the US National Institutes of Health–National Institute of General Medical Sciences–funded UCSD Genetics Training Program (T32 GM08666). This work was supported by the US National Institutes of Health and the Burroughs Wellcome Fund in Translational Research (J.G.G.). J.G.G. is an investigator with Howard Hughes Medical Institute.
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Lancaster, M., Louie, C., Silhavy, J. et al. Impaired Wnt–β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat Med 15, 1046–1054 (2009). https://doi.org/10.1038/nm.2010
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